We will develop new strains of Herpes simplex virus type-1 (HSV- 1) for use in the treatment of oral cancer. HSV- 1 has potential as a therapeutic tool for oral cancer since it infects oral epithelium as its natural host tissue, is highly cytotoxic, and spreads rapidly from one cell to another. The only disadvantage of HSV-1 is that it can spread to the nervous system, causing paralysis and death. To prevent this, we will develop a new strain of the virus whose replication is limited to oral cancer cells. This will be done by removing a promoter that controls expression of an essential viral gene, and replacing it with a promoter that is active in oral cancer cells but not in nervous- system cells. We will increase the anti-tumor effect of the virus by adding a gene for a cytokine. This will increase the local immune response to the infected tumor. We will then make the anti-tumor effect even stronger by exploiting the anti-tumor bystander effect that occurs when ganciclovir is activated by HSV-1. We expect that the triple combination of a tumor- restricted virus, enhanced local immune response, and anti-tumor bystander effect will be more effective in treatment of an experimental model of oral cancer than other treatments, and could lead to human trials in the future.